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The Concomitant Use of Clopidogrel and Proton Pump Inhibitors Linked to Adverse Outcomes
Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS. Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome. JAMA. 2009;301:937-944.
By Kim Farina, PhD
Introduction
New research data associates adverse outcomes with the use of Plavix® (clopidogrel) plus a proton-pump inhibitor (PPI) in patients discharged after hospitalization for acute coronary syndrome (ACS).1 Dual antiplatelet therapy, in the form. of clopidogrel and aspirin (ASA), has been traditionally prescribed to patients discharged from American hospitals with a diagnosis of ACS, including acute myocardial infarction (MI) or unstable angina (UA), to reduce the risk of death or recurrent ACS.1
ASA use is associated with the development of active peptic ulcers and other serious gastrointestinal (GI) or genitourinary bleeding; clopidogrel monotherapy to reduce these symptoms is not recommended.2,3 As a result, current guidelines advise physicians that, when prescribing dual antiplatelet therapy to patients with a history of GI bleeding, they should concomitantly prescribe drugs that reduce GI bleeding risk (e.g., PPIs).2,3
Available study data has provided conflicting evidence about the effects that PPIs taken in combination with clopidogrel have on clopidogrel effectiveness and patient risk for adverse outcomes.4-6 In light of this, the Society for Cardiovascular Angiography and Interventions and the American Heart Association issued statements providing guidance to physicians in the fall of 2008. In January 2009, the U.S. Food and Drug Administration acknowledged the issue in an Early Communication.9
The principle investigator of the Duke University Center for Education and Research on Therapeutics (CERT), Eric Peterson, participated in this retrospective Veterans Affairs (VA) database analysis that evaluated the outcomes of patients taking clopidogrel with or without a PPI after hospitalization for ACS. The findings of this retrospective cohort study were published in the March 4, 2009 Journal of the American Medical Association.1
Key Points
* This study assessed patient risk for the combined primary endpoint of all-cause mortality and rehospitalization for ACS (MI or UA) among 8205 ACS patients taking clopidogrel after discharge from a VA hospital. Nearly 64% (n = 5244) of those 8205 patients were also prescribed a PPI either at discharge or some time during the study's median 521-day follow-up period.
* Patients taking clopidogrel with PPI were at a higher risk for death or rehospitalization for ACS compared with patients taking clopidogrel alone (29.8%; n = 1561 vs. 20.8%; n = 615).
* The risk of death or rehospitalization for ACS increased during the periods that patients were taking clopidogrel and PPI vs. periods when patients were taking clopidogrel without a PPI (AHR 1.27; 95% CI, 1.10-1.46).
* Even though patients prescribed PPIs were older and had more comorbid conditions (e.g., diabetes, prior MI, CABG surgery, peripheral vascular disease, COPD, renal disease, dementia), the increased risk in the clopidogrel plus PPI group remained significant upon multivariable analysis (adjusted OR, 1.25; 95% CI, 1.11-1.41).
* Multivariable analysis of individual endpoints confirmed increased risks for recurrent ACS (AOR 1.86; 95% CI, 1.57-2.2) and revascularization procedures (AOR, 1.49; 95% CI, 1.30-1.71) associated with the use of clopidogrel with PPI, but not all-cause mortality (AOR, 0.91; 95% CI, 0.80-1.05).
* Nearly 60% of patients taking a PPI were prescribed omeprazole and 2.9% were prescribed rabeprazole. In combination with clopidogrel, both of these drugs were associated with an increased risk for adverse outcomes with no evidence of a dose-response relationship.
* There was a direct relationship between risk of adverse outcomes and increased time on clopidogrel plus PPI therapy.
* PPIs taken without clopidogrel did not increase the risk of death or rehospitalization for ACS among this study population. The authors commented, "when patients were not taking clopidogrel after hospital discharge, a prescription for PPI was not associated with death or rehospitalization for ACS, supporting the hypothesis that the interaction of PPI and clopidogrel, rather than PPI itself, was associated with increased adverse outcomes".1
Implications and Clinical Relevance
It is clear from this, and other studies, that a large percentage of patients receiving clopidogrel are concomitantly receiving a PPI. These findings suggest that, for patients on dual antiplatelet therapy who are at high-risk for GI bleeding, clinicians may need to rethink the therapeutic approach taken as more evidence emerges on the safety of using PPIs in combination with clopidogrel. However, there is not enough compelling evidence in existence to warrant a change in clinical practice at this time. Ho et al. comented, "pending additional evidence...the results of this study may suggest that PPIs should be used for patients with a clear indication for the medication, such as history of gastrointestinal tract bleeding, consistent with current guideline recommendations, rather than routine prophylactic prescription".1
Pantoprazole may be a prudent choice in the absence of additional evidence. Investigators of a Canadian population-based case-control study found an increased risk for recurrent MI in patients treated with clopidogrel plus omeprazole, lansoprazole, or rabeprazole but not in those treated with clopidogrel plus pantoprazole.4 Clopidogrel is a prodrug that requires cytochrome P450 isoenzymes, including P450 2C19, for activation. Unlike other PPIs, pantoprazole is not a cytochrome P450 2C19 inhibitor and therefore not a predicted suppressor of cytochrome P450-mediated clopidogrel metabolism. Physicians may also consider alternative gastric acid suppressors for patients requiring clopidogrel.
References
1. Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS. Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome. JAMA. 2009;301:937-944.
2. Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FKL, Furberg CD, Johnson DA, Mahaffey KW, Quigley EM. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2008:52:1502-17.
3. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE II, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardio. 2007;50:e1-157.
4. Juurlink DN, Gomes, T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009;180(7). DOI:10.1503/cmaj.082001.
5. Aubert RE, Epstein RS, Teagarden JR, et al. Abstract 3998: Proton pump inhibitors' effect on clopidogrel effectiveness: The Clopidogrel Medco Outcomes Study. Circulation. 2008;118:S815.
6. Dunn SP, Macaulay TE, Brennan DM, et al. Abstract 3999: Baseline proton pump inhibitor use is associated with increased cardiovascular events with and without the use of clopidogrel in the CREDO trial. Circulation. 2008;118:S815a.
7. Society for Cardiovascular Angiography and Interventions (SCAI). The Society for Cardiovascular Angiography and Interventions statement on possible interaction between anti-clotting medications and a type of heartburn medication. http://www.scai.org/pr.aspx?PAGE_ID=5763. Issued November 25, 2008. Accessed March 12, 2009.
8. American Heart Association, American College of Cardiology, and American College of Gastroenterology. American College of Cardiology (ACC)/American College of Gastroenterology (ACG)/American Heart Association (AHA) joint comment on studies regarding possible interaction of clopidogrel and proton pump inhibitors. http://americanheart.mediaroom.com/index.php?s=43&item=611. Issued November 11, 2008. Accessed March 12, 2009.
9. Food and Drug Administration. Early communication about ongoing safety review of clopidogrel bisulfate (marketed as Plavix). http://www.fda.gov/Cder/drug/ear ... grel_bisulfate.htm. Published January 26, 2009. Accessed March 11, 2009.
March 12, 2009
The Concomitant Use of Clopidogrel and Proton Pump Inhibitors Linked to Adverse Outcomes
Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS. Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome. JAMA. 2009;301:937-944.
By Kim Farina, PhD
Introduction
New research data associates adverse outcomes with the use of Plavix® (clopidogrel) plus a proton-pump inhibitor (PPI) in patients discharged after hospitalization for acute coronary syndrome (ACS).1 Dual antiplatelet therapy, in the form. of clopidogrel and aspirin (ASA), has been traditionally prescribed to patients discharged from American hospitals with a diagnosis of ACS, including acute myocardial infarction (MI) or unstable angina (UA), to reduce the risk of death or recurrent ACS.1
ASA use is associated with the development of active peptic ulcers and other serious gastrointestinal (GI) or genitourinary bleeding; clopidogrel monotherapy to reduce these symptoms is not recommended.2,3 As a result, current guidelines advise physicians that, when prescribing dual antiplatelet therapy to patients with a history of GI bleeding, they should concomitantly prescribe drugs that reduce GI bleeding risk (e.g., PPIs).2,3
Available study data has provided conflicting evidence about the effects that PPIs taken in combination with clopidogrel have on clopidogrel effectiveness and patient risk for adverse outcomes.4-6 In light of this, the Society for Cardiovascular Angiography and Interventions and the American Heart Association issued statements providing guidance to physicians in the fall of 2008. In January 2009, the U.S. Food and Drug Administration acknowledged the issue in an Early Communication.9
The principle investigator of the Duke University Center for Education and Research on Therapeutics (CERT), Eric Peterson, participated in this retrospective Veterans Affairs (VA) database analysis that evaluated the outcomes of patients taking clopidogrel with or without a PPI after hospitalization for ACS. The findings of this retrospective cohort study were published in the March 4, 2009 Journal of the American Medical Association.1
Key Points
* This study assessed patient risk for the combined primary endpoint of all-cause mortality and rehospitalization for ACS (MI or UA) among 8205 ACS patients taking clopidogrel after discharge from a VA hospital. Nearly 64% (n = 5244) of those 8205 patients were also prescribed a PPI either at discharge or some time during the study's median 521-day follow-up period.
* Patients taking clopidogrel with PPI were at a higher risk for death or rehospitalization for ACS compared with patients taking clopidogrel alone (29.8%; n = 1561 vs. 20.8%; n = 615).
* The risk of death or rehospitalization for ACS increased during the periods that patients were taking clopidogrel and PPI vs. periods when patients were taking clopidogrel without a PPI (AHR 1.27; 95% CI, 1.10-1.46).
* Even though patients prescribed PPIs were older and had more comorbid conditions (e.g., diabetes, prior MI, CABG surgery, peripheral vascular disease, COPD, renal disease, dementia), the increased risk in the clopidogrel plus PPI group remained significant upon multivariable analysis (adjusted OR, 1.25; 95% CI, 1.11-1.41).
* Multivariable analysis of individual endpoints confirmed increased risks for recurrent ACS (AOR 1.86; 95% CI, 1.57-2.2) and revascularization procedures (AOR, 1.49; 95% CI, 1.30-1.71) associated with the use of clopidogrel with PPI, but not all-cause mortality (AOR, 0.91; 95% CI, 0.80-1.05).
* Nearly 60% of patients taking a PPI were prescribed omeprazole and 2.9% were prescribed rabeprazole. In combination with clopidogrel, both of these drugs were associated with an increased risk for adverse outcomes with no evidence of a dose-response relationship.
* There was a direct relationship between risk of adverse outcomes and increased time on clopidogrel plus PPI therapy.
* PPIs taken without clopidogrel did not increase the risk of death or rehospitalization for ACS among this study population. The authors commented, "when patients were not taking clopidogrel after hospital discharge, a prescription for PPI was not associated with death or rehospitalization for ACS, supporting the hypothesis that the interaction of PPI and clopidogrel, rather than PPI itself, was associated with increased adverse outcomes".1
Implications and Clinical Relevance
It is clear from this, and other studies, that a large percentage of patients receiving clopidogrel are concomitantly receiving a PPI. These findings suggest that, for patients on dual antiplatelet therapy who are at high-risk for GI bleeding, clinicians may need to rethink the therapeutic approach taken as more evidence emerges on the safety of using PPIs in combination with clopidogrel. However, there is not enough compelling evidence in existence to warrant a change in clinical practice at this time. Ho et al. comented, "pending additional evidence...the results of this study may suggest that PPIs should be used for patients with a clear indication for the medication, such as history of gastrointestinal tract bleeding, consistent with current guideline recommendations, rather than routine prophylactic prescription".1
Pantoprazole may be a prudent choice in the absence of additional evidence. Investigators of a Canadian population-based case-control study found an increased risk for recurrent MI in patients treated with clopidogrel plus omeprazole, lansoprazole, or rabeprazole but not in those treated with clopidogrel plus pantoprazole.4 Clopidogrel is a prodrug that requires cytochrome P450 isoenzymes, including P450 2C19, for activation. Unlike other PPIs, pantoprazole is not a cytochrome P450 2C19 inhibitor and therefore not a predicted suppressor of cytochrome P450-mediated clopidogrel metabolism. Physicians may also consider alternative gastric acid suppressors for patients requiring clopidogrel.
References
1. Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS. Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome. JAMA. 2009;301:937-944.
2. Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FKL, Furberg CD, Johnson DA, Mahaffey KW, Quigley EM. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2008:52:1502-17.
3. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE II, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardio. 2007;50:e1-157.
4. Juurlink DN, Gomes, T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009;180(7). DOI:10.1503/cmaj.082001.
5. Aubert RE, Epstein RS, Teagarden JR, et al. Abstract 3998: Proton pump inhibitors' effect on clopidogrel effectiveness: The Clopidogrel Medco Outcomes Study. Circulation. 2008;118:S815.
6. Dunn SP, Macaulay TE, Brennan DM, et al. Abstract 3999: Baseline proton pump inhibitor use is associated with increased cardiovascular events with and without the use of clopidogrel in the CREDO trial. Circulation. 2008;118:S815a.
7. Society for Cardiovascular Angiography and Interventions (SCAI). The Society for Cardiovascular Angiography and Interventions statement on possible interaction between anti-clotting medications and a type of heartburn medication. http://www.scai.org/pr.aspx?PAGE_ID=5763. Issued November 25, 2008. Accessed March 12, 2009.
8. American Heart Association, American College of Cardiology, and American College of Gastroenterology. American College of Cardiology (ACC)/American College of Gastroenterology (ACG)/American Heart Association (AHA) joint comment on studies regarding possible interaction of clopidogrel and proton pump inhibitors. http://americanheart.mediaroom.com/index.php?s=43&item=611. Issued November 11, 2008. Accessed March 12, 2009.
9. Food and Drug Administration. Early communication about ongoing safety review of clopidogrel bisulfate (marketed as Plavix). http://www.fda.gov/Cder/drug/ear ... grel_bisulfate.htm. Published January 26, 2009. Accessed March 11, 2009.
March 12, 2009
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